Breast cancer is the most frequently diagnosed cancer in women and is the leading cause of female cancer- related deaths worldwide. In the majority of patients, death is not caused by the primary tumor but rather by metastases. Notably, interactions between malignant mammary cells and the surrounding peritumor stroma play a critical role in mammary tumor progression. Our data support the hypothesis that stromal type III collagen (Col3) plays a novel and important role in suppressing breast cancer progression. Specifically, our studies indicate that Col3 haploinsufficient (Col3+/-) mice develop significantly more metastases compared to wild-type littermates and that these Col3-deficient mice are more susceptible to aggressive local recurrence. The potential for Col3-directed therapies to prevent local and distant recurrence is supported by our ability to suppress aggressive behaviors of both murine and human triple negative breast cancer (TNBC) models in vitro and in vivo through application of exogenous Col3. The central hypothesis of this proposal is that Col3 prevents breast cancer metastasis and local recurrence by directly suppressing the aggressive behavior of breast cancer cells and preventing the formation of a tumor-permissive stroma. Identification of Col3 loss as a biologic driver of aggressive TNBC behaviors could dramatically improve patient outcomes by 1) ultimately exploiting regional Col3-associated stromal signatures as a prognostic biomarker to risk stratify patients, thus preventing overtreatment of low-risk patients and 2) developing Col3-containing biomaterials as a non-toxic therapy to decrease TNBC recurrence in high-risk patients. In this proposal, we will determine whether regional loss of Col3 is associated with invasion and established tumor permissive stromal features in human TNBC biopsies (Aim 1) and whether delivering Col3 via novel biomaterials to breast cancer resection sites will provide a safe, effective strategy to limit or eliminate aggressive cancer local regrowth and metastasis (Aim 2). Together, this work will provide unique insight into the role of Col3 in regulating progression of breast cancer, which may be relevant to many other types of metastatic and locally aggressive forms of cancers. Because Col3-containing biomaterials have been used safely in humans for other regenerative therapies, the proposed high risk/high impact studies have the potential to yield unique, rapidly translatable and safe diagnostic and therapeutic tools to improve both quality of care and prognosis of patients with breast cancer.